Gastric cancer is a deadly disease that is estimated to be the second leading cause of cancer deaths worldwide. The disease varies greatly in incidence rate, both geographically and among different ethnic groups. In the United States, certain ethnic groups, such as Hispanics in Texas and other Southwestern states, have a higher incidence rate than the U.S. population of Northern European descent. Multiple genetic changes contribute to the development of many common cancers. These changes include (l) mutations in proto-oncogenes, such that the genes become amplified or overexpressed to increase cellular proliferation; (2) mutations in tumor suppressor genes, which decrease rates of cellular growth in their unaltered state; and (3) mutations in genes which regulate overall genomic stability, probably by affecting correction of replication errors. The genetic alterations taking place in the course of development of gastric cancer are not well characterized. The focus of this proposal is the investigation of tumor suppressor genes affected in gastric cancer. In order to search for sites in the human genome which are likely to contain tumor suppressor genes, this laboratory has previously analyzed gastric tumors for loss of heterozygosity (LOH) at polymorphic sites on each arm of each autosome throughout the genome. This work has revealed elevated rates of LOH at sites near the TP53 gene (as expected) and at sites on chromosomes 3p and on l2q. As an extension of this study, the present proposal contains the following aims: (1) to map the smallest common deletion among affected tumor cases by using additional genetic markers from chromosomes 3p and l2q; (2) to analyze microdissected pre- malignant areas for the presence of the same genetic lesions observed in the adjacent tumor; (3) to test the functional significance of the l2q sites by chromosome transfer experiments. Microcells containing chromosome 12 and fragments of l2q will be fused with gastric cancer cell lines lacking the part of chromosome l2q containing the putative tumor suppressor gene(s). Subsequent reduction in the tumorigenicity of the gastric cancer cells in nude mice will be taken as evidence supporting the existence on chromosome 12q of a tumor suppressor gene affected in gastric cancer. identification of the specific suppressor genes involved in the genesis of gastric cancer is an important first step in a pathway that will lead to an understanding the biology of the protein products of those genes. Since these proteins are likely to participate critically in reducing cell proliferation the study of each of them holds the potential to reveal more specific therapies for cancer.